People & Ideas
Nina Cabezas Wallscheid is a group leader at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany. Taking a multidisciplinary approach, her lab investigates the mechanisms by which metabolites regulate the epigenetic and metabolic state of hematopoietic stem cell fate in young and upon aging, with the aim to identify therapeutic strategies for nutritional and hematological diseases.
In this issue of JEM, companion articles from Pinilla et al. and Robinson et al. demonstrate that ribotoxic stress induced by P. aeruginosa and C. diphtheriae EEF2-targeting exotoxins leads to NLRP1 inflammasome activation, representing a new mechanism of effector-triggered immunity.
Michelson and colleagues continue to advance our understanding of self-antigen representation by medullary thymic epithelial cells, identifying a new role for Hnf4γ in the regulation of thymic mimetic cells as well as their peripheral counterparts.
In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher. As well as being able to celebrate the positives of becoming an independent researcher, we would also like to use this platform to discuss the unique challenges they face as women scientists in their respective scientific environments.
Maizels and Gause review advances in type 2 immunity in the setting of helminth worm infections, in the skin, lung, and intestinal tract, requiring the orchestration of adaptive immunity to concentrate innate effector cells and mechanisms in scale and focus at the site of infection.
Brief Definitive Reports
Here, Pinilla and colleagues address the ability of the human NLRP1 inflammasome-forming sensor to detect translation inactivation by bacterial toxins in healthy and cystic fibrosis airway and corneal epithelial cells.
This work demonstrates that diphtheria toxin is a potent trigger for the ZAKα-dependent ribotoxic stress response and the NLRP1 inflammasome in human skin cells. ZAKα inhibition is effective at limiting the skin damage caused by diphtheria toxin in vitro.
This report identifies a central role for type I interferons in governing the activation and effector functions of murine and human MAIT cells during pulmonary infection with Klebsiella pneumoniae.
While inflammatory Th17 cells produce IFN-γ under the circumstances of both autoimmunity and infection, they display distinct transcriptional and metabolic features. Understanding these differences can facilitate the selective targeting of disease-promoting Th17 cells in autoimmune treatment without compromising infection clearance.
eTregs are crucial to control inflammation caused by their analogous Teff counterparts. However, excessive eTreg responses could also be detrimental in certain disease settings. This study identifies miR-15/16 clusters as key posttranscriptional regulators in limiting eTreg differentiation and function through targeting IRF4 and neuritin, respectively.
Technical Advances and Resources
Combining whole-tissue imaging and single-cell RNA sequencing datasets, Tauber et al. present a pan-organ analysis of mast cells in mice and humans at steady state, revealing an unexpected heterogeneity of mast cell populations across tissues and species.
Michelson et al. show that the transcription factor Hnf4 upregulates gut and liver self-antigens within thymic epithelial cells via an enhancer-driven mechanism, mirroring peripheral development within the thymus to enable immunological tolerance toward the gut and liver.
Single-cell profiling reveals unique features of diabetogenic T cells in anti-PD-1-induced type 1 diabetes mice
Collier et al. identify unique features of diabetogenic T cells in the pancreas and peripheral tissues between anti-PD-1-induced type 1 diabetes (T1D) and spontaneous T1D in non-obese diabetic mice and provide a rationale for monitoring immune-related adverse events in the blood.
FOXO1 orchestrates the intestinal homeostasis via neuronal signaling in group 3 innate lymphoid cells
Prof. Wang and colleagues reveal that FOXO1 coordinates gut neuronal signal and immune response of ILC3s. FOXO1-related regulation of VIPR2 and ADRA2A signaling pathways balance the activation of ILC3s under steady conditions or during colitis independently of T cells. Chronic stress elevates cAMP level and downregulates FOXO1 level in ILC3s, exacerbating intestinal inflammation.
IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation
Petersone et al. investigate IL-21–dependent germinal center (GC) regulation and reveal key roles for IL-21 in promoting light zone GC B cell selection and controlling dark zone GC B cell proliferation by upregulation of cyclin D3.
Oncolytic viruses induce tumor lysis and inflame the tumor microenvironment but do not relieve immunosuppressive signals. Engineering oncolytic vaccinia virus to express a potent TGFβR inhibitor results in local neutralization of TGFβ, increased Treg cell fragility, and superior therapeutic response.
We show that tumor-derived IL-6 blocks the development of type 1 classical dendritic cells through the induction of C/EBPβ in the common dendritic cell progenitor, which supports Zeb2 expression in the −165 kb enhancer, thereby preventing pre-cDC1 specification.
Sandhow et al. here have in transplantation-induced AML mouse models demonstrated the leukemia-regenerating capacity of AML cells infiltrated in the skin and the role of skin mesenchymal niches in maintaining/protecting AML cells, providing new insight into the pathology of leukemia cutis.
Chen et al. develop an algorithm to map enzyme-substrate-recognizing motif mutations in cancer and find BUD13 AGC kinase motif mutations fuel colon cancer growth by inactivating the tumor suppressive E3 ligase Fbw7 via novel mechanisms.